Journal
MOLECULAR BIOLOGY OF THE CELL
Volume 17, Issue 3, Pages 1322-1330Publisher
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E05-06-0507
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Funding
- MRC [G0400678, G0100200] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/C514458/1] Funding Source: Medline
- Medical Research Council [G0400678, G0100200] Funding Source: Medline
- Wellcome Trust [066100, 063661] Funding Source: Medline
- Biotechnology and Biological Sciences Research Council [BB/C514458/1] Funding Source: researchfish
- Medical Research Council [G0400678, G0100200] Funding Source: researchfish
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The tight junction adaptor protein ZO-1 regulates intracellular signaling and cell proliferation. Its Src homology 3 (SH3) domain is required for the regulation of proliferation and binds to the Y-box transcription factor ZO-1-associated nucleic acid binding protein (ZONAB). Binding of ZO-1 to ZONAB results in cytoplasmic sequestration and hence inhibition of ZONAB's transcriptional activity. Here, we identify a new binding partner of the SH3 domain that modulates ZO-1-ZONAB signaling. Expression screening of a cDNA library with a fusion protein containing the SH3 domain yielded a cDNA coding for Apg-2, a member of the heat-shock protein 110 (Hsp 110) subfamily of Hsp70 heat-shock proteins, which is overexpressed in carcinomas. Regulated depletion of Apg-2 in Madin-Darby canine kidney cells inhibits G(1)/S phase progression. Apg-2 coimmunoprecipitates with ZO-1 and partially localizes to intercellular junctions. junctional recruitment and coirnmunoprecipitation with ZO-1 are stimulated by heat shock. Apg-2 competes with ZONAB for binding to the SH3 domain in vitro and regulates ZONAB's transcriptional activity in reporter gene assays. Our data hence support a model in which Apg-2 regulates ZONAB function by competing for binding to the SH3 domain of ZO-1 and suggest that Apg-2 functions as a regulator of ZO-1-ZONAB signaling in epithelial cells in response to cellular stress.
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